EP0796271B1 - Dipeptidische p-amidinobenzylamide mit n-terminalen sulfonyl- bzw. aminosulfonylresten - Google Patents

Dipeptidische p-amidinobenzylamide mit n-terminalen sulfonyl- bzw. aminosulfonylresten Download PDF

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Publication number
EP0796271B1
EP0796271B1 EP95941015A EP95941015A EP0796271B1 EP 0796271 B1 EP0796271 B1 EP 0796271B1 EP 95941015 A EP95941015 A EP 95941015A EP 95941015 A EP95941015 A EP 95941015A EP 0796271 B1 EP0796271 B1 EP 0796271B1
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EP
European Patent Office
Prior art keywords
alkyl
aryl
cycloalkyl
formula
hydrogen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP95941015A
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German (de)
English (en)
French (fr)
Other versions
EP0796271A1 (de
Inventor
Hans Joachim BÖHM
Stefan Koser
Helmut Mack
Thomas Pfeiffer
Werner Seitz
Hans Wolfgang Höffken
Wilfried Hornberger
Thomas Zierke
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Abbott GmbH and Co KG
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BASF SE
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K5/00Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08Tripeptides
    • C07K5/0802Tripeptides with the first amino acid being neutral
    • C07K5/0812Tripeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K5/00Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06Dipeptides
    • C07K5/06008Dipeptides with the first amino acid being neutral
    • C07K5/06017Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06026Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K5/00Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06Dipeptides
    • C07K5/06008Dipeptides with the first amino acid being neutral
    • C07K5/06017Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • C07K5/06043Leu-amino acid
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K5/00Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06Dipeptides
    • C07K5/06008Dipeptides with the first amino acid being neutral
    • C07K5/06078Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K5/00Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06Dipeptides
    • C07K5/06104Dipeptides with the first amino acid being acidic
    • C07K5/06113Asp- or Asn-amino acid
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides

Definitions

  • the present invention relates to dipeptidic p-amidinobenzylamides with N-terminal sulfonyl or aminosulfonyl residues, their Production and their use as thrombin inhibitors.
  • WO 93/11152 describes linear amidino-containing thrombin inhibitors, which can also contain a sulfonamide group.
  • EP 601 459 describes linear and heterocyclic thrombin inhibitors, which have a sulfonamide group.
  • aryl denotes mono- or bicyclic aromatic Groups which contain 6 to 10 carbon atoms in the ring system, e.g. Phenyl or naphthyl, and with up to three identical or different Substituents can be provided.
  • heteroaryl refers to 5- or 6-membered aromatic rings containing 1 or 2 heteroatoms such as N, O or S. can and to which an aryl ring can be fused.
  • residues R 1 , A and B are linked to one another as shown in structure I, the amino acid residues in A preferably (D) -configured and the amino acid residues in B preferably (L) -configured.
  • the compounds of formula I as such or in the form of their salts with physiologically acceptable acids are: hydrochloric acid, citric acid, tartaric acid, Lactic acid, phosphoric acid, methanesulfonic acid, acetic acid, Formic acid, maleic acid, fumaric acid, maleic acid, succinic acid, Hydroxy succinic acid, sulfuric acid, glutaric acid, Aspartic acid, pyruvic acid, benzoic acid, glucuronic acid, Oxalic acid, ascorbic acid and acetylglycine.
  • the invention further relates to the intermediates of the formula IV wherein R 1 , A and B have the meaning given and which can be used to prepare the compounds I.
  • the compounds I can be prepared starting from the ⁇ -amino acid HA-OH or from the N-protected cyclic amino acid B-OH according to reaction scheme I or II.
  • R 7 H or C 1 -C 4 alkyl
  • R 8 C 1 -C 4 alkyl, preferably methyl or t-butyl
  • R 9 CN or and P is a protecting group, preferably t-butoxycarbonyl (Boc) or benzyloxycarbonyl (Cbz).
  • the protected amino acids PA-OH and HB-OR 8 can be coupled to the dipeptide PAB-OR 8 and then reacted after splitting off P with R 1 SO 2 Cl or from R 8 with p-cyano- or p-amidinobenzylamine, the reaction sequence can be any.
  • R 1 -SO 2 -A-OH can also be coupled directly with para-HB-NHCH 2 C 6 H 4 R 9 to the end product I or intermediate IV.
  • Boc protective groups are removed hydrogenolytically with HCl / dioxane or CF 3 COOH / methylene chloride, Cbz protective groups or with HF.
  • the saponification of ester functions is carried out with NaOH or LiOH in an alcoholic solvent such as methanol or ethanol.
  • t-Butyl esters are saponified with acids, for example CF 3 COOH.
  • reaction with the sulfonyl chlorides R 1 -SO 2 Cl in the presence of an organic base such as triethylamine, pyridine or N, N-diisopropylethylamine is carried out in organic solvents such as CH 2 Cl 2 , THF or DMF.
  • organic solvents such as CH 2 Cl 2 , THF or DMF.
  • the reaction is carried out in the presence of aqueous alkali metal hydroxide or carbonate solutions.
  • amidines are prepared from the nitrile precursors by the classic Pinner synthesis (R. Roger and DG Neilson, Chem. Rev. 1961, 61 , 179) or preferably by a modified Pinner synthesis which proceeds as an intermediate via iminothioester salts (H. Vieweg et al., Pharmacy 1984, 39 , 226).
  • the catalytic hydrogenation of N-hydroxyamidines, which are accessible by adding hydroxylamine to the cyano group, with Raney Ni or Pd / C in alcoholic solvents also leads to amidines (BJ Broughton et al., J. Med. Chem. 1975, 18 , 1117 ).
  • the new compounds can be used for therapy and prophylaxis of all diseases in which thrombin plays a role plays. These are particularly thromboembolic disorders such as Myocardial infarction, peripheral arterial occlusive disease, deep Venous thrombosis, pulmonary embolism and stroke. Furthermore they can help prevent reocclusion after opening arterial vessels used by mechanical methods or lysis become.
  • the compounds according to the invention can be administered orally in the usual way or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally, rectally).
  • parenterally subcutaneously, intravenously, intramuscularly, intraperitoneally, rectally.
  • the application can also be used with Vapors or sprays are done through the nasopharynx.
  • the dosage depends on the age, condition and weight of the patient as well as on the type of application.
  • the daily is Active ingredient dose per person between about 10 and 2000 mg oral administration and between approximately 1 and 200 mg with parenteral administration. This dose can be given in 2 to 4 single doses or once a day Depot form can be given.
  • the new compounds can be used in the usual galenic Application forms can be used in solid or liquid form, e.g. as Tablets, film-coated tablets, capsules, powders, granules, coated tablets, Suppositories, solutions, ointments, creams or sprays. These will made in the usual way.
  • the active ingredients can the usual pharmaceutical auxiliaries such as tablet binders, fillers, Preservatives, tablet disintegrants, flow regulators, Plasticizers, wetting agents, dispersing agents, Emulsifiers, solvents, retardants, antioxidants and / or propellant gases are processed (see H. Sucker et al: Pharmaceutical Technology, Thieme-Verlag, Stuttgart, 1978).
  • the application forms thus obtained contain the active ingredient usually in an amount of 0.1 to 99 percent by weight.
  • the crude product was hydrogenated under a slight excess pressure of hydrogen in a mixture of 40 ml of methanol and 5 ml of glacial acetic acid with a spatula tip of 10% palladium on carbon at 50 ° C. After 5.5 h, the catalyst was filtered off, the solution was evaporated in vacuo and codistilled several times with methanol and toluene. After stirring the resulting product several times from DCM, 1.5 g (73% of theory over 3 steps) of clean N-hydroxysulfonyl-D-phenylalanyl-proline (p-amidinobenzyl) -amide were obtained, which according to NMR was present as betaine. Mp: 220-224 ° C, white powder, FAB-MS: 474 (MH) + .
  • the core consists of 9 parts corn starch, 3 parts milk sugar and 1 part of Luviskol® VA 64 (vinylpyrrolidone-vinyl acetate copolymer 60: 40, cf. Pharm. Ind. 1962, 586).
  • the saccharification mass consists of 5 parts of cane sugar, 2 parts of corn starch, 2 parts calcium carbonate and 1 part talc. The so produced Dragees are then given an enteric-coated tablet Provide cover.
  • Example 1 100 g of the substance of Example 1 are placed in 5000 ml of water Addition of NaCl dissolved and adjusted to pH 6.0 with 0.1 N NaOH, so that a blood isotonic solution arises. 5 ml each Solution are filled into ampoules and sterilized.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Plant Substances (AREA)
  • Polysaccharides And Polysaccharide Derivatives (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Saccharide Compounds (AREA)
  • Enzymes And Modification Thereof (AREA)
EP95941015A 1994-12-06 1995-11-25 Dipeptidische p-amidinobenzylamide mit n-terminalen sulfonyl- bzw. aminosulfonylresten Expired - Lifetime EP0796271B1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE4443390 1994-12-06
DE4443390A DE4443390A1 (de) 1994-12-06 1994-12-06 Neue dipeptidische p-Amidinobenzylamide mit N-terminalen Sulfonyl- bzw. Aminosulfonylresten
PCT/EP1995/004646 WO1996017860A1 (de) 1994-12-06 1995-11-25 Neue dipeptidische p-amidinobenzylamide mit n-terminalen sulfonyl- bzw. aminosulfonylresten

Publications (2)

Publication Number Publication Date
EP0796271A1 EP0796271A1 (de) 1997-09-24
EP0796271B1 true EP0796271B1 (de) 2000-02-02

Family

ID=6535046

Family Applications (1)

Application Number Title Priority Date Filing Date
EP95941015A Expired - Lifetime EP0796271B1 (de) 1994-12-06 1995-11-25 Dipeptidische p-amidinobenzylamide mit n-terminalen sulfonyl- bzw. aminosulfonylresten

Country Status (20)

Country Link
US (1) US5852051A (ja)
EP (1) EP0796271B1 (ja)
JP (1) JPH10509727A (ja)
CN (1) CN1168673A (ja)
AT (1) ATE189458T1 (ja)
AU (1) AU699579B2 (ja)
BR (1) BR9509970A (ja)
CA (1) CA2207874A1 (ja)
CZ (1) CZ153797A3 (ja)
DE (2) DE4443390A1 (ja)
ES (1) ES2143666T3 (ja)
FI (1) FI972384A0 (ja)
HU (1) HU222353B1 (ja)
IL (1) IL116231A (ja)
MX (1) MX9704050A (ja)
NO (1) NO972559L (ja)
RU (1) RU2152953C1 (ja)
TW (1) TW336222B (ja)
WO (1) WO1996017860A1 (ja)
ZA (1) ZA9510295B (ja)

Families Citing this family (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE9900043D0 (sv) * 1999-01-11 1999-01-11 Astra Ab New use
US5705487A (en) * 1994-03-04 1998-01-06 Eli Lilly And Company Antithrombotic agents
US5707966A (en) * 1994-03-04 1998-01-13 Eli Lilly And Company Antithrombotic agents
US5726159A (en) * 1994-03-04 1998-03-10 Eli Lilly And Company Antithrombotic agents
US5914319A (en) * 1995-02-27 1999-06-22 Eli Lilly And Company Antithrombotic agents
US5710130A (en) * 1995-02-27 1998-01-20 Eli Lilly And Company Antithrombotic agents
SE9602263D0 (sv) 1996-06-07 1996-06-07 Astra Ab New amino acid derivatives
US6200967B1 (en) 1996-06-25 2001-03-13 Eli Lilly And Company Anticoagulant agents
US5863929A (en) * 1996-06-25 1999-01-26 Eli Lilly And Company Anticoagulant agents
AR013084A1 (es) 1997-06-19 2000-12-13 Astrazeneca Ab Derivados de amidino utiles como inhibidores de la trombina, composicion farmaceutica, utilizacion de dichos compuestos para la preparacion demedicamentos y proceso para la preparacion de los compuestos mencionados
SE9704543D0 (sv) 1997-12-05 1997-12-05 Astra Ab New compounds
WO2000061608A2 (de) * 1999-04-09 2000-10-19 Basf Aktiengesellschaft Niedermolekulare inhibitoren von komplementproteasen
EP1182207B1 (en) * 2000-08-11 2007-04-18 Dendreon Corporation Non-covalent inhibitors of urokinase and blood vessel formation
WO2002014349A2 (en) * 2000-08-11 2002-02-21 Corvas International, Inc. Non-covalent inhibitors of urokinase and blood vessel formation
DE10049937A1 (de) * 2000-10-06 2002-04-11 Knoll Ag Niedermolekulare Inhibitoren von Serinproteasen mit Polyhydroxyalkyl- und Polyhydroxycycloalkylresten
CH695999A5 (de) 2002-02-28 2006-11-15 Wilex Ag Verfahren zur Herstellung von 3- Amidinophenylalanin-Derivaten.
DE102004029812A1 (de) * 2004-06-19 2006-05-24 Clariant Gmbh Verfahren zur Herstellung von Nitrilen aus Aldehydoximen durch Umsetzung mit Alkylphosphonsäureanhydriden

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE9103612D0 (sv) * 1991-12-04 1991-12-04 Astra Ab New peptide derivatives
AU675981B2 (en) * 1992-12-02 1997-02-27 Bristol-Myers Squibb Company Guanidinyl-substituted heterocyclic thrombin inhibitors
SE9301916D0 (sv) * 1993-06-03 1993-06-03 Ab Astra New peptides derivatives
CA2140598C (en) * 1994-01-27 2010-03-09 Masahiro Ohshima Prolineamide derivatives
ZA951617B (en) * 1994-03-04 1997-02-27 Lilly Co Eli Antithrombotic agents.

Also Published As

Publication number Publication date
NO972559L (no) 1997-08-05
RU2152953C1 (ru) 2000-07-20
CZ153797A3 (cs) 1998-02-18
FI972384A (fi) 1997-06-05
IL116231A0 (en) 1996-03-31
AU4255996A (en) 1996-06-26
AU699579B2 (en) 1998-12-10
ZA9510295B (en) 1997-06-05
HUT77289A (hu) 1998-03-30
DE59507755D1 (de) 2000-03-09
DE4443390A1 (de) 1996-06-13
CN1168673A (zh) 1997-12-24
ES2143666T3 (es) 2000-05-16
IL116231A (en) 2001-01-28
NO972559D0 (no) 1997-06-05
TW336222B (en) 1998-07-11
MX9704050A (es) 1997-08-30
FI972384A0 (fi) 1997-06-05
HU222353B1 (hu) 2003-06-28
US5852051A (en) 1998-12-22
EP0796271A1 (de) 1997-09-24
ATE189458T1 (de) 2000-02-15
JPH10509727A (ja) 1998-09-22
CA2207874A1 (en) 1996-06-13
WO1996017860A1 (de) 1996-06-13
BR9509970A (pt) 1997-11-25

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